| Summary: | 碩士 === 國立臺灣師範大學 === 化學系 === 100 === In the present study, we carried out docking computation of compounds against two kinases, CDK2 and c-MET, using GOLD program. Both are of pharmaceutical interest.
In the part of CDK2 kinase, we investigated if allowing side chains to move and applying hydrogen bond constrains can enhance enrichment factor(EF) in virtual screening. To this end, compounds from DUD database were used for benchmark. The computations gave that applying hydrogen bond constraints enhance EF, on average, by about a factor of 2, and allowing side chains to move only enhance EF slightly. With both effects turned on in docking computation, the calculated EFs do not enhance significantly compared with EFs obtained from individual effect. Interestingly, some side chains have more significant enrichment effects than others. These computed results should be useful for virtual screening over large compounds databases against CDK2 kinase in order to obtain better hits.
In addition to CDK2, we also investigated c-MET kinase using similar docking procedure. c-MET (MET) is a kinase protein that plays an important role in multi-cells, including regulation of proliferation, motility, invasion, migration, and angiogenesis. It is also essential for embryonic development and tissue damage repair. However, overexpression of c-MET or mutations occurs in many human cancers.
First, we carried out docking computations for 10 c-met inhibitor complexes with crystal structures available in the protein data bank in orderto examine their reproducibility.Second, we choose 5 complexes to do crossing docking and investigate how ligand conformations can be regained when protein structures from different complexes were used. Third, we selected top3 protein structures from these 5 complexes for subsequent virtual screening. For benchmark, we constructed a group of 1000 compounds consisting 10 active and 990 decoy compounds, and see if 10 active compounds can be screened out in docking computation.Effects of side chain flexibility and hinge hydrogen bond constraints were examined as well. We found that the results obtained byallowing 3 residues to move and constraining2hinge hydrogen bonds simultaneouslyare better than results obtained by other combinations. Finally, virtual screening for 400,000 compounds of c-MET was carried out. The interactions between top-ranked compounds and c-met were analyzed and discussed. These computed results and analysis should be of aid in design and discovery of c-met inhibitors.
key words:kinase、docking computations、Virtual Screening
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